Perampanel is a pharmaceutical active ingredient, currently in clinical phase 3, used in the treatment of Parkinson's disease, epilepsy and multiple sclerosis.
Perampanel, having the following chemical formula
is also known as E 2007, ER 155055-90 and 3-(2-Cyanophenyl)-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one.There are various known synthesis routes of this molecule, such as those reported in patent publications EP1300396, EP1465626, EP1772450, EP1764361 and EP1970370.Many of the synthesis routes of this active ingredient reported in the prior art employ the key intermediate 2-(1,3,2-dioxaborinane-2-yl)benzonitrile having the following chemical formula:
or employ the synthetic precursor thereof called 2-cyanophenylboronic acid of formula (I):
The 2-(1,3,2-dioxaborinane-2-yl)benzonitrile is indeed quantitatively prepared by simple esterification with 1,3-propanediol of the 2-cyanophenylboronic acid of formula (I), as well reported in the prior art.
There are several synthesis routes of the 2-cyanophenylboronic acid of formula (I). From an industrial viewpoint, the most interesting process to date for the preparation of this compound is the process described in patent publication US2009/0184289 wherein, starting from Benzonitrile, n-butyllithium and 2,2,6,6-tetramethylpiperidine at −78° C. are employed to generate the ortho-anion which, by reacting with triisopropoxyborane and subsequent acid hydrolysis of the diisopropyl ester of the 2-cyanophenylboronic acid obtained, gives the desired product. The highest molar yield reported is 71%. This process appears to be an improvement with respect to the process described in the Organic Letters of 2001, Vol. 3, no. 10, pages 1435-1437. This process however, has obvious disadvantages, such as the need to operate in cryogenic conditions (T=−78° C.) using special equipment, while obtaining the product in relatively low molar yield. The product also contains an impurity typical of that synthetic process.
The Journal of Organometallic Chemistry (2002), 653 (1-2), 269-278 reports the synthesis of the pharmaceutical active ingredient called E2040 by means of the compound of formula (I) or an ester thereof, of which there is mention and description of and the preparation of the key intermediate 2-(1,3,2-dioxaborinane-2-yl)benzonitrile by means of esterification with 1,3-propanediol by the compound of formula (I). The preparation of the compound of the formula (I) is carried out by ortho-bromobenzonitrile with a halogen/lithium exchange and attachment of the anion onto the trimethoxyborane, followed by hydrolysis of the dimethyl ester. A yield of about 50% is reported, which for industrial purposes is of little interest.